This is an application for a K23 for Dr. Patrick Pun, who is a nephrologist and Assistant Professor at Duke University Medical Center. Dr. Pun is establishing himself as a young investigator in patient- oriented clinical research on sudden cardiac death (SCD) in chronic kidney disease (CKD) patients. Through a structured career development plan including formal didactic training in genetic epidemiology and quantitative genetics, mentoring by a dedicated group of accomplished senior investigators and collaborators, and the conduct original research examining unique risk factors for SCD among a large population of patients with moderate CKD, this award will provide Dr. Pun the resources, training and protected time to become a an independent clinical researcher in the field of cardiorenal disease. Dr. Pun's mentoring team includes his primary mentor, Dr. Laura Svetkey (Director of the Duke Hypertension Center and the Vice Chair for Faculty development in the Duke Department of Medicine), and two co-mentors, Dr. John Middleton (Director of Clinical Research in the Duke Division of Nephrology) and Dr. Svati Shah (Associate Professor of Medicine, Center for Human Genetics). CKD affects more than 29 million Americans; compared the general population, these patients have a markedly increased risk of SCD. The precise nature of how CKD promotes SCD risk is not well understood, and traditional cardiovascular risk factors do not adequately explain SCD risk. The overall objective of this application is to identif CKD patients at high risk of malignant arrhythmias and SCD, so that these patients might be targeted for intervention. The central hypothesis of this proposal is that cardiac conduction problems related to serum electrolyte disturbances, genetic influences and resting ECG abnormalities play an important role in determining SCD risk in patients with moderate CKD (CKD stage 3-4). Combining and linking a large prospective longitudinal research database containing clinical data and outcomes from more than 35,000 patients with cardiovascular disease, a genetic biorepository, and extensive medical records, the application contains the following specific aims: (1) To evaluate associations between serum electrolyte levels (potassium, calcium and magnesium) and SCD risk in moderate CKD patients; (2) To evaluate associations between common variants in pro-arrhythmic genes and risk of significant ventricular arrhythmias and SCD in moderate CKD patients; and (3) To evaluate associations between resting ECG measurements of ventricular conduction (QRS duration, QTc interval) and SCD risk in the setting of CKD. Since SCD mechanisms in high-risk CKD patients are poorly understood, this contribution will be significant because it may elucidate mechanisms of disease, provide novel tools for risk stratification and monitoring, and identify specific potentia targets for SCD prevention.
More than 29 million Americans have chronic kidney disease, and these individuals are among the highest risk group for sudden cardiac death. An improved understanding of the mechanisms and risk factors implicated in these conditions could lead to important interventions and therapies to prevent the catastrophic outcomes from this disease.
